In vivo investigation of the tissue response to commercial Teflon insulin infusion sets in large swine for 14 days: the effect of angle of insertion on tissue histology and insulin spread within the subcutaneous tissue

Eisler, Gabriella; Kastner, Jasmin R; Torjman, Marc C.; Khalf, Abdurizzagh; Diaz, David R.; Dinesen, Alek R; Loeum, Channy; Thakur, Mathew L.; Strasma, Paul; Joseph, Jeffrey I.

doi:10.1136/bmjdrc-2019-000881

Cited by 14 publications

(17 citation statements)

References 27 publications

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“…Although several factors might induce inflammation at the infusion site, the specific mechanisms underlying CSII device failure have yet to be determined. Various hypotheses have been generated including mechanical barriers to insulin flow and direct toxicity from the infusion device's composition 12,15,16,28 . However, this study focused on the root causes of the inflammatory response, specifically the phenolic compound used in insulin formulations, as well as the specific cell types responsible for the inflammation induced by these insulin phenolic compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Various hypotheses have been generated including mechanical barriers to insulin flow and direct toxicity from the infusion device's composition. 12,15,16,28 However, this study focused on the root causes of the inflammatory response, specifically the phenolic compound used in insulin formulations, as well as the specific cell types responsible for the inflammation induced by these insulin phenolic compounds. These studies demonstrated that commercial insulin formulations containing phenolic compounds are highly cytotoxic.…”

Section: Day 7 Insulin Infusion In Diabetic Micementioning

confidence: 99%

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Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges

Kesserwan

Mulka

Sharafieh

et al. 2020

J Biomedical Materials Res

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Continuous Subcutaneous Insulin Infusion (CSII) is superior to conventional insulin therapy as it improves glycemic control thus reducing the probability of diabetic complications. Notwithstanding CSII's benefits, insulin dependent diabetic patients rarely achieve optimal glucose control. Moreover, CSII is only FDA approved for 3 days and often fails prematurely for reasons that have not been fully elucidated. We hypothesize that phenolic compounds, such as m‐cresol and phenol, which are present in all commercial insulin formulations are responsible for the tissue reaction occurring at the insulin infusion site. This hypothesis was examined with in vitro cell cultures and a mouse air‐pouch model to determine cellular and tissue reactions following infusions with saline, phenolic compounds, (i.e., commercial diluent), and insulin. We demonstrated that diluent and insulin were cytotoxic to cells in culture at sub‐clinical concentrations (e.g., >1:10 of commercial insulin). Air pouch studies demonstrated that infusion of either diluted insulin or diluent itself induced three to five‐fold level of recruited leukocytes as compared to saline. At both 3‐ and 7‐days post infusion, these were predominantly neutrophils and macrophages. We conclude that phenolic compounds in commercial insulin preparations are cell and tissue toxic, which contributes to the failure of effective insulin infusion therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Day 7 Insulin Infusion In Diabetic Micementioning

confidence: 99%

Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges

Kesserwan

Mulka

Sharafieh

et al. 2020

J Biomedical Materials Res

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“…[1][2][3][4] The reasons for unexplained hyperglycemia remain unknown, although several hypotheses propose local inflammation of the subcutaneous tissue at the infusion site as a likely cause. [5][6][7][8][9][10][11] Continuous glucose monitors (CGM) are also long-dwelling, subcutaneously placed devices augmenting pump therapy, which have faced challenges in maintaining patency over time due to localized inflammation. [12][13][14] Multiple efforts to temper such inflammation through the use of locally administered anti-inflammatory agents, such as corticosteroids, have been reported with some success.…”

Section: Introductionmentioning

confidence: 99%

“…1 -4 The reasons for unexplained hyperglycemia remain unknown, although several hypotheses propose local inflammation of the subcutaneous tissue at the infusion site as a likely cause. 5 -11…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Insulin Lispro Pharmacokinetics and Pharmacodynamics Over 10 Days of Continuous Insulin Infusion in People With Type 1 Diabetes

Garhyan

Pratt

Klein

et al. 2022

J Diabetes Sci Technol

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Background: We evaluated the effect of meloxicam on insulin lispro pharmacokinetics and glucose pharmacodynamics over 10 days of continuous subcutaneous insulin infusion (CSII) at one infusion site in people with type 1 diabetes (T1D). Method: This phase 1, randomized, double-blind, single-center, two-way crossover study enrolled adults with T1D for ≥1 year on stable CSII for ≥3 months. Participants randomly received U100 insulin lispro and LY900027 (U100 insulin lispro + 0.25 mg/mL meloxicam). Primary end points were area under the insulin lispro curve from 0 to 5 hours (AUCIns.0-5h) after bolus administration prior to a mixed-meal tolerance test (MMTT) and maximum observed concentration of insulin lispro (CIns.max) on days 5, 7, and 10, versus day 3 (baseline). Results: A total of 20 participants were randomized. Insulin absorption was accelerated for insulin lispro and LY900027 from days 1 to 7. The AUCIns.0-5h was significantly lower on day 10 versus day 3 for LY900027 (−19%) and insulin lispro (−14%); the AUCIns.0-5h did not differ significantly between treatments. The CIns.max increased with LY900027 and insulin lispro (by ~14%-23% and ~16%-51%) on days 5, 7, and 10 versus day 3. The CIns.max of LY900027 was ~14%-23% lower than insulin lispro CIns.max on days 7 and 10 ( P ≤ .0805). Accelerated insulin absorption and a modest loss of total insulin exposure led to a loss of MMTT glycemic control at later time points. Conclusions: The pharmacokinetics of insulin changed over catheter wear time even when an anti-inflammatory agent was present. Postprandial glycemic control was adversely affected by the accelerated insulin absorption and decreased insulin exposure.

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“…Cumulatively, the catheter material, shape, size, insulin aggregates/amyloids, and the infused preservative in an insulin formulation could all contribute to the FBR. Other challenges include the exposed wound, the catheter insertion device, the catheter’s needle, and perhaps the catheter insertion angle. − FBR at an insulin device location cumulatively contributes to local skin irritation due to leukocyte recruitment and activation of the inflammatory cascade. Independent of the initiating source(s) of inflammatory cell recruitment, accumulation of leukocytes and associated proteases at insulin infusion sites could lead to increased insulin uptake and/or insulin degradation by inflammatory cells leading to an exacerbation of the inflammatory response and ultimately altering insulin absorption and blood glucose control.…”

mentioning

confidence: 99%

Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia

Mulka

Lewis

et al. 2021

ACS Pharmacol. Transl. Sci.

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Background: Exogenous insulin therapy requires stabilization of the insulin molecule, which is achieved through the use of excipients (e.g., phenolic preservatives (PP)) that provide protein stability, sterility and prolong insulin shelf life. However, our laboratory recently reported that PP, (e.g., m-creosol and phenol) are also cytotoxic, inducing inflammation and fibrosis. Optimizing PP levels through filtration would balance the need for insulin preservation with PP-induced inflammation. Method: Zeolite Y (Z-Y), a size-exclusion-based resin, was employed to remove PP from commercial insulin formulations (Humalog) before infusion. Results: PP removal significantly decreased cell toxicity in vitro and inflammation in vivo. Infusion site histological analysis after a 3 day study demonstrated that leukocyte accumulation increased with nonfiltered preparations but decreased after filtration. Additional studies demonstrated that a Z-Y fabricated filter effectively removed excess PP such that the filtered insulin solution achieved equivalent glycemic control in diabetic mice when compared to nonfiltered insulin. Conclusion: This approach represents the proof of concept that using Z-Y for in-line PP removal assists in lowering inflammation at the site of insulin infusion and thus could lead to extending the functional lifespan of insulin infusion sets in vivo.

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In vivo investigation of the tissue response to commercial Teflon insulin infusion sets in large swine for 14 days: the effect of angle of insertion on tissue histology and insulin spread within the subcutaneous tissue

Cited by 14 publications

References 27 publications

Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges

Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges

Evaluation of Insulin Lispro Pharmacokinetics and Pharmacodynamics Over 10 Days of Continuous Insulin Infusion in People With Type 1 Diabetes

Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia

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